We have previously shown that GABAARs in ILS mice exhibit ethanol potentiation while ethanol had no effect on GABAARs in hippocampi of ISS mice. Similarly, preliminary data presented in this proposal show that ethanol potentiates the GABAAR in cortex of ILS but not ISS mice and inhibits the NMDAR in hippocampus and cortex of ILS but not ISS mice. These dramatic differences in ILS and ISS mice in terms of the ability of ethanol to affect the GABAAR and NMDAR in hippocampus and cortex will be the principal focus of our proposal. We are proposing to study the molecular mechanisms that underlie the differences in ethanol sensitivity of the GABAAR and NMDAR in ILS and ISS mice. We anticipate that these two strains of mice will thus provide us with a unique opportunity to test hypotheses about these mechanisms. This will be the principal goal of the proposed studies. In pursuit of this goal our proposal will have three Specific Aims. Aim #1. Test the hypothesis that differences in the phosphorylation of the NMDAR and/or GABAAR in ILS and ISS mice may underlie the differences in ethanol effects on these receptors in the two strains of mice. We and others have recently shown that phosphorylation may play an important role in the ethanol sensitivity of the NMDAR and the GABAAR. And, we have shown that GABAAR and NMDAR of ILS mice are sensitive to ethanol and those of ISS mice are not. Therefore, in this aim we will compare the basal and ethanol-stimulated phosphorylation of specific subunits and/or phosphosites of the NMDAR and GABAAR in ILS and ISS mice. Aim #2. Test the hypothesis that differences in the ethanol sensitivity of the trafficking mechanisms for the NMDAR and/or GABAAR in ILS and ISS mice may underlie the differences in ethanol effects on these receptors in the two strains of mice. We and others have shown that NMDAR and GABAAR membrane trafficking may play important roles in the function of these receptors. Moreover, we have recently obtained preliminary data that ethanol reduces membrane surface expression of the NMDAR in ILS but not in ISS mice. Therefore, in this aim we will confirm and extend this observation by comparing the basal and ethanol- stimulated surface expression of the NMDAR and GABAAR in ILS and ISS mice. Aim #3 Test the hypothesis that interventions that modulate phosphorylation and/or surface expression of the NMDAR and GABAAR will reduce the effect of ethanol on GABAA R and NMDAR responses in ILS mice and and "rescue" ethanol effects on these receptors in ISS mice. Based on results from Aims 1 and 2 above, we will intervene to pharmacologically modulate phosphorylation and/or surface expression. We will then test these interventions to determine whether the biochemical differences seen in Aims 1 and 2 or either necessary or sufficient to explain the differences in ethanol effects on the evoked responses of these receptors in ILS and ISS mice.